9-benzoyl-1,2,3,4-tetrahydrocarbazole

ABSTRACT

9-Benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole and 9-benzoyl-3-(N-phenylcarbamoyloxymethyl)-1,2,3,4-tetrahydrocarbazole, having respectively antiinflammatory and antibacterial activities, and their preparation are described.

CROSS-REFERENCES TO RELATED APPLICATIONS

This application is a continuation-in-part of copending application Ser.No. 514,767, filed Oct. 15, 1974, now U.S. Pat. No. 3,948,939, issuedApr. 6, 1976, in turn a continuation-in-part of application Ser. No.314,099, filed Dec. 11, 1972, now U.S. Pat. No. 3,905,998, issued Sept.16, 1975, in turn a continuation-in-part of Ser. No. 200,205, filed Nov.18, 1971, now U.S. Pat. No. 3,758,496, issued Sept. 11, 1973, in turn acontinuation-in-part of Ser. No. 42,620, filed June 2, 1970, now U.S.Pat. No. 3,687,969, issued Aug. 29, 1972.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention relates to 9-benzoyl-3-(CH₂OY)-1,2,3,4-tetrahydrocarbazoles.

2. Description of the Prior Art

9-Benzoyl-1,2,3,4,-tetrahydrocarbazoles, having antiphlogistic,analgesic, antifebric and sedative properties, are described in BritishPatent Specification No. 1,183,093, published Mar. 4, 1970.4-Hydroxymethyl-9-methyl-1,2,3,4-tetrahydrocarbazole, an intermediatefor corresponding 4-aminomethyl compounds, is described in U.S. Pat. No.3,752,823, issued Aug. 14, 1973.

SUMMARY OF THE INVENTION

The invention provides a composition of matter defined as a9-benzoyl-3-(CH₂ OY)-1,2,3,4-tetrahydrocarbazole of the formula ##STR1##wherein Y is hydrogen or N-phenylcarbamoyl.

The compound of the invention having formula I wherein Y is hydrogen wasfound to be useful as an antiinflammatory agent when tested inpharmacological test procedures described hereinbelow.

The compound of the invention having formula I wherein Y isN-phenylcarbamoyl was found to be useful as an antibacterial agent whentested as described hereinbelow.

DETAILED DESCRIPTION OF THE INVENTION

The molecular structures of the compounds of the invention were assignedon the basis of the method of their synthesis and study of theirinfrared spectra, and confirmed by the correspondence between calculatedand found values for the elementary analysis.

The compounds of the invention were prepared as follows:

EXAMPLE 1 9-Benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole (formulaI, Y=hydrogen)

1-Benzoyl-1-phenylhydrazine hydrochloride (23.8 g.) and 18 g. of4-hydroxymethylcyclohexanone ethylene ketal in 450 ml. of absolute ethylalcohol was heated under reflux for four hours. The chilled mixture wasfiltered, the filtrate was evaporated to dryness under reduced pressureand the resulting residue was dissolved in ether. The ether solution waswashed with water, dilute hydrochloric acid, water, dilute sodiumbicarbonate, and water, dried and evaporated to dryness to give, afterrecrystallization from ethyl acetate-hexane, 9.6 g. of9-benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole; m.p. 105°-107° C.

Preparation of 4-Hydroxymethylcyclohexanone ethylene ketal

Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml. ethylene glycol and21 g. of p-toluenesulfonic acid in 5.5 liters of benzene were heated atreflux with stirring for 24 hours while water was separated by means ofa water trap. The mixture was cooled and poured into 4 liters of icewater. The benzene layer was separated, washed with 1 liter of 5% sodiumbicarbonate, 1 liter of water and 1 liter of saturated sodium chloridesolution, dried and evaporated to dryness to give, after distillation,245.6 g. of ethyl cyclohexanone-4-carboxylate ethylene ketal; b.p.95°-99.5° C. (0.07 mm.); n²⁵ D 1.4620. A solution of 35 g. of theketal-ester in 50 ml. of dry tetrahydrofuran was added dropwise to 5.7g. of lithium aluminum hydride in 250 ml. of dry tetrahydrofuran, andthe mixture was heated at reflux for five hours and cooled to roomtemperature. A saturated sodium chloride solution (11.4 ml.) was addeddropwise and heating at reflux was continued for one hour. The mixturewas cooled and filtered, and the filtrate was dried and evaporated todryness to give 26.9 g. of 4-hydroxymethylcyclohexanone ethylene ketalas a clear, colorless oil which was used without further purification.

EXAMPLE 29-Benzoyl-3-(N-phenylcarbamoyloxymethyl)-1,2,3,4-tetrahydrocarbazole(formula I, Y = N-phenylcarbamoyl)

9-Benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole (9.8 g.) andphenylisocyanate (4.2 g.) were combined and heated on a steam bath forone and one-half hours. The mixture was cooled and triturated in etherand the resulting solid was collected by filtration and washed withether to give 7.1 g. of the title compound; m.p. 140°-143° C.

The antiinflammatory activity of9-benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole was determined byits ability to inhibit in rats carrageenin-induced foot edema andadjuvant-induced arthritis. A brief description of the pharmacologicaltest procedures employed follows.

Inhibition of Carrageenin-Induced Foot Edema in Rats

Young male rats weighing 100-110 g. are used. Food is withdrawnapproximately 18 hours prior to medication but the animals are permittedfree access to drinking water up to the time of medication. Drugs to betested are suspended by triturating in 1% gum tragacanth using groundglass homogenizers and administered by gavage in a volume of 1 ml/100 gbody weight. Control animals receive the gum tragacanth only. One hourafter medication, 0.05 ml of 1% suspension of carrageenin in 0.9% salineis injected into the plantar tissue of the left hind paw. Three hoursafter injection of the carrageenin, edema formation, i.e., increase infoot volume (difference between left hind paw and the uninjected righthind paw) is measured plethysmographically in the unanesthetized rat.

Inhibition Adjuvant-Induced Arthritis in Rats

Adult male rats weighing 200-230 grams are used. Adjuvant (M.butyricum), 0.1 ml of a 0.6% suspension in heavy mineral oil, isinjected into the plantar tissue of the left hind paw. A negativecontrol group is injected with mineral oil only. Beginning on the ninthday after adjuvant injection (polyarthritis does not appear untilapproximately the tenth day after adjuvant administration), the animalsreceive 6 daily medications of test compound suspended by triturating in1% gum tragacanth using a ground glass homogenizer and administered bygavage in a volume of 1 ml/100 g body weight. Both the negative controland adjuvant injected control animals receive the vehicle only. Food andwater are permitted ad libitum. Twenty-four hours after the lastmedication, the animals are weighed, the degree of arthriticinvolvement, i.e., increase in foot volume and plasma inflammation unitsare determined. Foot volume is measured plethysmographically in theunanesthetized rat.

9-Benzoyl-3-hydroxymethyl-1,2,3,4-tetrahydrocarbazole was found to beactive when tested in rats at 100 mg./kg. of body weight in theInhibition of Carrageenin-Induced Foot Edema and Adjuvant-InducedArthritis Test Procedures described above and is indicated for use as anantiinflammatory agent. This compound can be prepared for use byfollowing conventional pharmaceutical procedures; that is, it can beincorporated in unit dosage form in tablets or capsules for oraladministration either alone or in combination with suitable adjuvantssuch as calcium carbonate, starch, lactose, talc, magnesium stearate,gum acacia, and the like; or as an aqueous or oil suspension or solutionin a pharmaceutically acceptable vehicle such as aqueous alcohol,glycol, oil solution or oil water emulsion for oral or parenteraladministration.

9-Benzoyl-3-(N-phenylcarbamoyloxymethyl)-1,2,3,4-tetrahydrocarbazole,when tested in the Autotiter method described by Goss et al., AppliedMicrobiology 16 (No. 9), 1414- 1416 (1968), was found to beantibacterially effective against Pseudomonas aeruginosa at aconcentration of 125 mcg./ml. thus indicating the utility of thiscompound as an antibacterial agent against Pseudomonas aeruginosa. Thiscompound may be formulated for use by conventional procedures, e.g., forapplication to inanimate surfaces; it can be formulated as a dilutesolution in an aqueous medium or in a solution containing a surfactantand is applied to the surface to be disinfected by conventional meanssuch as spraying, swabbing, immersion and the like.

We claim: 1.9-Benzoyl-3-(N-phenylcarbamoyloxymethyl)-1,2,3,4-tetrahydrocarbazole.